Many compounds of pharmaceutical interest face challenges during the process of drug development because of their pharmacokinetic or pharmacodynamic properties and also due to their poor solubility.
Molecular modifications of a drug substance are designed to enhance, amongst other aspects, the specificity for a particular target site, increasing its potency, improving its rate and extent of absorption, modifying the time span in which the drug becomes bio-available in the body while preserving the efficacy and toxicity value of the drug. There are limited number of chemical modifications known which can enhance aqueous solubility of the drug substance independent of pH or which can alter the pharmacokinetic properties of drugs without affecting its efficacy and toxicity.
It is interesting to note that, attempts to improve solubility of pharmaceutical compounds such as taxanes based on molecular modification have not resulted in any successful clinical products. Certain prodrugs of Taxol have been prepared which are purported to undergo in vivo transformation into Taxol and some other product. For instance, PCT patent publication no. WO 1997044063 discloses certain prodrugs but appears that these compounds still do not have the desired pharmacokinetic properties. Pharmaceutical industry majorly depends on novel formulations or excipients to generate a desirable solubility profile for molecules of biological interest to develop them for clinical use.
Some alkaloids having a purine or pyrimidine base type structures have been known in the prior art for the molecular modification of drug species for site specific drug delivery.
For instance, EP0110955 B1 discloses a compound of Formula [D-DHC] for the site specific/sustained delivery of a centrally acting drug species to the brain. The compound on administration gets converted to quaternized salt inside the body where it is locked inside the brain only and the salt entering other parts of the body gets excreted readily from liver and kidney. Thus, the concentration of quaternary salt is higher in brain as compared to the other parts of the body.
There is still a need to develop better prodrugs or modified compounds having improved solubility and/or pharmacokinetic properties for the effective drug delivery without loss of therapeutic efficacy and increase in toxicity of active molecule or drug.